Phenylalkanoic acid derivatives which have heretofore been known, are disclosed respectively in Japanese Patent Gazette No. Sho 58-4699 or 4699/83 (hereinafter referred to as Prior Art 1) and Japanese Pat. Appln. Laid-0pen Gazette No. Sho 54-103852 or 103852/79 (hereinafter referred to as Prior Art 2).
The Prior Art 1 concretely discloses 2-[4-(2-oxocyclopentane-1-yl methyl)phenyl]propionic acid, 4-(2-oxocyclopentane-1-yl methyl)phenylacetic acid, 2-[4-(2-oxocyclohexane-1-yl methyl)phenyl]propionic acid, 4-(2-oxocyclohexane-1-yl methyl)phenylacetic acid and the like and reports that these compounds have anti-inflammatory, analgesic and anti-febrile actions.
On the other hand, the Prior Art 2 widely describes phenylacetic acid derivatives represented by the following formula (P) ##STR2## wherein m is an integer of 1-5, &gt;A--B-- is &gt;CH--CH.sub.2 --, &gt;C.dbd.CH-- or &gt;CH--CO--, R.sup.5 is a hydrogen atom, halogen atom, trifluoromethyl group, nitro group or amino group, R.sup.6 and R.sup.7 are each a hydrogen atom or lower alkyl group or they together form an ethylene group, X.sup.3 is two hydrogen atoms or oxo, and Y.sup.5 is cyano, hydroxyamidocarbonyl, carbamoyl, 5-tetrazolyl, carboxyl, a salt thereof with a physiologically acceptable base, an ester thereof with a physiologically safe alcohol or an amide thereof with a physiologically safe amine.
The general formula (P) in the Prior Art 2 prima facie partly covers the phenylalkanoic acid derivatives of this invention, but the Prior Art 2 only describes concretely, as compounds similar to the derivatives of this invention, 2-(4-cyclopentylmethylphenyl)-propionic acid, 4-(cyclopentylmethyl)-phenylacetic acid, 2-(3-chloro-4-cyclopentylmethylphenyl)-propionic acid, 2-(4-cyclohexylmethylphenyl)-propionic acid, 2-(4-cyclopentylmethyl-3-nitrophenyl)-propionic acid, 2-[4-(2-oxopentylidenemethyl)-phenyl]-propionic acid, 2-(4-cyclopentylidenemethyl)-phenyl-propionic acid, and the like.
In addition, the patent application laid open in the Prior Art 2 (said Pat. Appln. Laid-Open Gazette No. Sho 54-103852) has already been published under Patent Gazette No. Hei 1-34980 or 34980/89 claiming a right to lndane-1-carboxylic acid derivatives, not to phenylalkanoic acid derivatives at all.
As mentioned above, the Prior Art 2 does not concretely disclose anything about the phenylalkanoic acid derivatives of this invention and only vaguely expresses such compounds in a higher technical concept. Thus, the Prior Arts 1 and 2 do not concretely disclose anything about the phenylalkanoic acid derivatives of this invention and, further, they do not disclose that said derivatives have remarkable analgesic and anti-inflammatory actions with very little side effects. Further, the compounds concretely disclosed in the Prior Arts 1 and 2 do not have sufficient analgesic and anti-inflammatory or antiphlogistic actions without hardly raising any problems as to their side effects.
Accordingly, the phenylalkanoic acid derivatives of this invention described later are novel compounds which have remarkable effects and have been specially selected among very many compounds expected from the general formula (P) described as a higher technical concept particularly in the Prior Art 2.
In addition, ibuprofen, loxoprofen, ketoprofen and the like have been known as non-steroid type acidic antiphlogistic agents having a phenylalkanoic acid as their partial structure. These non-steroid type compounds are appreciated to be very different in physiological profile (or properties) from each other depending on the kind of a substituent attached to the para- or meta-position of a phenylalkanoic acid.
Japanese Patent Gazette No. Hei 1-35806 or 35806/89 (hereinafter referred to as Prior Art 3) and Japanese Pat. Appln. Laid-Open Gazette No. Sho 60-78844 or 178844/85 (hereinafter referred to as Prior Art 4) report on 2-[4-(2-hydroxycyclopentane-1-yl methyl)phenyl]propionic acid and 2-[4-(2-hydroxycyclohexyl methyl)phenyl]propionic acid. These compounds so reported are also recognized to have large effects on physiological profile due to slight structural differences in stereocoordination. In short, these Prior Arts have found that a compound having analgesic and antiphlogistic actions can be obtained by selecting a substituent at the paraposition in a phenylalkanoic acid. These above facts substantiate that a slight change in the chemical structure of a medicine will have great effects on the physiological profile thereof, but said Prior Arts neither disclose nor even suggest anything at all about a concept that a phenylalkanoic acid is enhanced in its physiological profile by further introducing other substituents onto the benzene ring of the phenylalkanoic acid.
The aforementioned Prior Arts 3 and 4 describe stereoisomers or optical isomers, which are (2S)-2-[4-(2-hydroxycyclopentane-1-yl methyl)phenyl] propionic acid and 2-[4-(2-hydroxycyclohexyl methyl)phenyl] propionic acid. These isomeric compounds are described in said Prior Arts to have analgesic and anti-inflammatory (antiphlogistic) actions, but their efficacy is not sufficient.
Ibuprofen, flurbiprofen, loxoprofen, alminoprofen, alclofenac and the like which are known as phenylalkanoic acid-type non-steroid analgesic and anti-inflammatory drugs, will be rapidly absorbed through digestive canals when they are administered as oral drugs, thereby to exert analgesic and anti-inflammatory actions.
According to clinical reports on side effects of the above non-steroid type medicines, however, these medicines when orally taken will have side effects such as digestive canal troubles, dropsy, cutaneous troubles and sleepiness.
Further, a non-steroid acidic anti-inflammatory drug (Acidic NSAID) typified by aspirin or indomethacin is also known, but it has less serious side effects than steroid while it is not appreciated to have sufficient effects on chronic inflammations such as rheumatism and deformation arthritis (or osteoarthritis). Further, whereas the acidic NSAID exerts slight side actions as compared with the steroid, it very often shows side effects such as intestinal canal trouble.
In view of such conventional technical problems as above, this invention has been made.
An object of this invention is to provide novel excellent phenylalkanoic acid derivatives which exhibit further remarkable antiphlogistic and analgesic actions as compared with said conventional phenylalkanoic acid-based non-steroid type antiphlogistic agents and have much less side effects such as gastro-intestinal tract trouble.
There are known methods for separating optical isomers which include a preferrential crystallization-out method, a diastereomer method and a chiral column operation method. These methods raise problems that they cannot provide enough optical purity to be used as a method for separating optical isomers from a phenylalkanoic acid derivative and they further need complicated treatments.
Further, as methods for separating optical isomers, there have recently be reported many methods utilizing asymmetry appreciating capability owned by organisms or enzymes. These methods are described in, for example, J. Chem. Soc., Commun., 148(1989) or J. Chem. Soc., Commun., 49(1990). At the present, however, since enzymes greatly vary in their selectivity or reactivity depending upon reaction conditions thereof or substrates therefor, general laws cannot be established. In other words, when an alkyl group, a halogen atom or the like which is apt to have solid (or three-dimensional) effects is present near the reaction site, an enzyme reaction may not satisfactorily proceed or may not proceed at all. Thus, at the present, the chemical structure of a substrate used, the kind, amount, reaction temperature and time of an enzyme used have great effects on the utilization of enzyme reaction. Accordingly, the above separating methods have been recognized as inappropriate to apply to such compounds having near the reaction site a substituent which is capable of exerting solid effects as the phenylalkanoic acid derivative of this invention. Thus, the separation of optical isomers of phenylalkanoic acid derivatives by using such separating methods as the above has been neither developed nor suggested.
Accordingly, another object of this invention is to provide a separating method for easily obtaining phenylalkanoic acid derivatives having high optical purity by conveniently separating the optical isomers of phenylalkanoic acid derivatives using high asymmetry appreciation capability owned by enzymes.